Lung cancer is the leading cause of cancer-related deaths worldwide, and SCLC comprises about 16% of all lung cancer cases in the United States (Travis et al. (1995) Cancer 75: 191-202). Currently, SCLC is diagnosed on the basis of gross morphological and histological data, and is too often identified after the disease has reached its advanced stages (Junker et al. (2000) J. Cancer Res. Clin. Oncol. 126: 361-368). Although there is a high response rate to present treatments consisting of high-dose chemotherapy with or without radiotherapy, disease recurrence is frequent, and tumors become resistant to these approaches, resulting in 2-year survival rates of only 6-12% (Johnson et al. (1998) J. Natl. Cancer Inst. (Bethesda) 90: 1335-1345). Considerable toxicity is also associated with these therapies.
The expression of the vasopressin gene is largely restricted to hypothalamic neurons, and it encodes for a protein product of ˜17 kDa, to which an N-glycosidic side-chain of ˜4 kDa is added, resulting in the ˜20 kDa provasopressin (pro-VP) precursor. This protein is normally packaged into secretory vesicles where it undergoes enzymatic cleavage to generate vasopressin (VP), VP-NP, and VAG (North, W. G. In: D. Gash and G. Boer (eds.), Vasopressin: Principles and Properties, pp. 175-209. New York: Plenum Press, 1987). These components are then secreted into the circulation. SCLC tumors and cultured cells also express the VP gene, however intact provasopressin protein can become localized to the cell surface plasma membrane (Friedmann et al. (1994) B. J. Cancer 69: 260-263; North et al. (1993) Ann. NY Acad. Sci. 689: 107-121). Polyclonal antibodies raised against VP-NP bind specifically to the surface of cultured SCLC cells, as determined by immunofluorescent analysis (Friedmann et al. (1995) Neuropeptides 28: 183-189; North et al. (1983) Prog. Brain Res. 60: 217-225; North and Yu (1993) Regulatory Peptides 45: 209-216). Thus, the target of these antibodies has been termed neurophysin-related cell surface antigen (NRSA) (North et al. (1993) Peptides 14: 303-307). Polyclonal anti-VP-NP antibodies recognize proteins of ˜20 kDa and ˜40 kDa in total protein extracts from SCLC cultured cells by Western analysis (North et al. (1993) Peptides 14: 303-307). The ˜20 kDa protein corresponds in size to the provasopressin protein, and the ˜40 kDa protein is believed to be a related form (Camier et al. (1979) FEBS Lett., 108: 369-373; Lauber et al. (1979) FEBS Lett., 97: 343-347; Lauber et al. (1981) Proc. Natl. Acad. Sci. USA, 78: 6086-6090; Moore and Rosenior. (1983) Prog. Brain Res., 60: 253-256; Nicolas et al. (1980) Proc. Natl. Acad. Sci. USA, 77: 2587-2591; Rosenior et al. (1981) Endocrinology, 109: 1067-1072). Polyclonal antibodies that have been raised against the vasopressin, VP-NP, or VAG regions of the pro-VP protein display specific staining of SCLC tumor sections, whereas they exhibit a very low incidence of immunoreactivity with the non-neuroendocrine tumors examined (Friedmann et al. (1994) B. J. Cancer 69: 260-263; Friedmann et al. (1993) Cancer Letters 75: 79-85).
Breast cancer is a leading cause of death among women throughout the world, and accounts for the death of approximately 50,000 women in the United States each year (American Cancer Society. Cancer Facts and Figures, Atlanta, Ga.: American Cancer Society, 1993). Although there have been many recent advances for effectively treating this disease (Silverstein, M. J. et al., The Breast Journal (2002) 8:70-76), successful intervention still heavily relies on early detection through mammography and surgical removal of cancerous tissue. As for small cell lung cancer (SCLC), products of the vasopressin (VP) gene appear to present a universal tumor marker system for breast cancer/ductal carcinoma in situ (DCIS) that could provide advanced warnings of early post-oncogenic tissue changes, precise methods for identifying and evaluating changes in tumor burden, and new non-surgical methods of treatment that are effective in providing long-term survival for patients (North et al. Br. Can. Res. Treat. (1995) 34: 229-235; and North Exper. Physiol. (2000) 85S: 27-40). Alternatively, no evidence has been found for expression by normal breast tissues or by various fibrocystic conditions, including atypical hyperdisplasia (North et al., Endocrin. Pathology, In Press, June, 2003). Expression of the VP gene in breast cancer gives rise to surface markers named GRSA (North Exper. Physiol. (2000) 85S: 27-40). These markers interact with polyclonal antibodies recognizing provasopressin and seem to have molecular weights of 40 and 20 kilodaltons. Since the antibodies were first found to interact with glycopeptide moiety of provasopressin, the antigen has been called GRSA (i.e., Glycopeptide-Related cell Surface Antigen).